The current proposal focuses on functional changes in immune/neural system interactions that impact on post-injury cellular plasticity. The short- term goal of these studies is to chronicle the basic mechanisms underlying age-related microglial changes in the normal degenerative/regenerative process over the life-span in a rodent model. The integration of these findings with studies of Alzheimer's disease currently underway could determine if microglia and their secretory products, along with beta- amyloid protein precursor (beta-APP) and its breakdown products, may work synergistically in a neurodegenerative cascade. The hypothesis underlying this proposal is that microglia mediate the degenerative/regenerative processes that follow deafferentation and axotomy, and that this is altered in the aged animal. Three Specific Aims have been devised to test this hypothesis. Specific Aim 1 involves a series of descriptive studies designed to fully characterize microglial anatomy, expression of markers reflective of activation, and production of secretory products in young, middle-aged and old mice. Specific Aim 2 will examine microglial responses to two different types of lesions (deafferentation and axotomy) with increasing age. Anatomical changes reflective of cellular plasticity, expression of microglial triggers and markers reflective of microglial activation, production of microglial secretory products, and the production and fate of beta-APP will be analyzed. Finally, Specific Aim 3 will manipulate elements of these responses in isolated microglial primary cell cultures derived from the various age and lesion experimental groups. The expression of markers reflective of microglial activation, production of microglial secretory products, and microglial proliferation and phagocytosis will be examined. These Specific Aims will be investigated using quantitative light and electron microscopy, polymerase chain reaction-based analyses, in situ hybridization, lesioning, primary cell culture, and combinations of these techniques. The proposed studies should provide insights into the types of changes that may underlie age-related, abnormal brain function.